Non-invasive brain stimulation for fibromyalgia: current trends and future perspectives.

Fibromyalgia, a common and enduring pain disorder, ranks as the second most prevalent rheumatic disease after osteoarthritis. Recent years have witnessed successful treatment using non-invasive brain stimulation. Transcranial magnetic stimulation, transcranial direct current stimulation, and electroconvulsion therapy have shown promise in treating chronic pain. This article reviews the literature concerning non-invasive stimulation for fibromyalgia treatment, its mechanisms, and establishes a scientific basis for rehabilitation, and discusses the future directions for research and development prospects of these techniques are discussed.

Simulated Gastric Acid Promotes the Horizontal Transfer of Multidrug Resistance Genes across Bacteria in the Gastrointestinal Tract at Elevated pH Levels.

The assessment of factors that can promote the transmission of antibiotic resistance genes (ARGs) across bacteria in the gastrointestinal tract is in great demand to understand the occurrence of infections related to antibiotic-resistant bacteria (ARB) in humans. However, whether acid-resistant enteric bacteria can promote ARG transmission in gastric fluid under high-pH conditions remains unknown. This study assessed the effects of simulated gastric fluid (SGF) at different pH levels on the RP4 plasmid-mediated conjugative transfer of ARGs. Moreover, transcriptomic analysis, measurement of reactive oxygen species (ROS) levels, assessment of cell membrane permeability, and real-time quantitative assessment of the expression of key genes were performed to identify the underlying mechanisms. The frequency of conjugative transfer was the highest in SGF at pH 4.5. Antidepressant consumption and certain dietary factors further negatively impacted this situation, with 5.66-fold and 4.26-fold increases in the conjugative transfer frequency being noted upon the addition of sertraline and 10% glucose, respectively, compared with that in the control group without any additives. The induction of ROS generation, the activation of cellular antioxidant systems, increases in cell membrane permeability, and the promotion of adhesive pilus formation were factors potentially contributing to the increased transfer frequency. These findings indicate that conjugative transfer could be enhanced under certain circumstances in SGF at elevated pH levels, thereby facilitating ARG transmission in the gastrointestinal tract. IMPORTANCE The low pH of gastric acid kills unwanted microorganisms, in turn affecting their inhabitation in the intestine. Hence, studies on the factors that influence antibiotic resistance gene (ARG) propagation in the gastrointestinal tract and on the underlying mechanisms are limited. In this study, we constructed a conjugative transfer model in the presence of simulated gastric fluid (SGF) and found that SGF could promote the dissemination of ARGs under high-pH conditions. Furthermore, antidepressant consumption and certain dietary factors could negatively impact this situation. Transcriptomic analysis and a reactive oxygen species assay revealed the overproduction of reactive oxygen species as a potential mechanism by which SGF could promote conjugative transfer. This finding can help provide a comprehensive understanding of the bloom of antibiotic-resistant bacteria in the body and create awareness regarding the risk of ARG transmission due to certain diseases or an improper diet and the subsequent decrease in gastric acid levels.

Predicting the concentrations of enteric viruses in urban rivers running through the city center via an artificial neural network.

Viral waterborne diseases are widespread in cities due largely to the occurrence of enteric viruses in urban rivers, which pose a significant concern to human health. Yet, the application of rapid detection technology for enteric viruses in environmental water remains undeveloped globally. Here, multiple linear regression (MLR) modeling and artificial neural network (ANN) modeling, which used frequently measured physicochemical parameters in river water, were constructed to predict the concentration of enteric viruses including human enteroviruses (EnVs), rotaviruses (HRVs), astroviruses (AstVs), noroviruses GⅡ (HuNoVs GⅡ), and adenoviruses (HAdVs) in rivers. After training, testing, and validating, ANN models showed better performance than any MLR model for predicting the viral concentration in Jinhe River. All determined R-values for ANN models exceeded 0.89, suggesting a strong correlation between the predicted and measured outputs for target enteric viruses. Furthermore, ANN models provided a better congruence between the observed and predicted concentrations of each virus than MLR models did. Together, these findings strongly suggest that ANN modeling can provide more accurate and timely predictions of viral concentrations based on frequent (or routine) measurements of physicochemical parameters in river water, which would improve assessments of waterborne disease prevalence in cities.

Decreased Antibiotic Susceptibility in Pseudomonas aeruginosa Surviving UV Irradition.

Given its excellent performance against the pathogens, UV disinfection has been applied broadly in different fields. However, only limited studies have comprehensively investigated the response of bacteria surviving UV irradiation to the environmental antibiotic stress. Here, we investigated the antibiotic susceptibility of Pseudomonas aeruginosa suffering from the UV irradiation. Our results revealed that UV exposure may decrease the susceptibility to tetracycline, ciprofloxacin, and polymyxin B in the survival P. aeruginosa. Mechanistically, UV exposure causes oxidative stress in P. aeruginosa and consequently induces dysregulation of genes contributed to the related antibiotic resistance genes. These results revealed that the insufficient ultraviolet radiation dose may result in the decreased antibiotic susceptibility in the pathogens, thus posing potential threats to the environment and human health.

Contamination sources of the enteric virus in recreational marine water shift in a seasonal pattern.

Human enteric virus occurrence in bathing beaches poses a potential health risk to swimmers. They may come from several sources, but the understanding of the seasonal contribution of contamination sources to virus occurrence is still lacking. Here, the surveillance of human enteric viruses at the First Bathing Beach in Qingdao was performed January-December 2018. The occurrence of Enteric viruses, assayed with quantitative polymerase chain reaction (qPCR), was analyzed at temporal and spatial levels to determine the viral contamination sources. The results showed that only Astroviruses (AstVs) and Adenoviruses (HAdVs) were found in the swimming area. Their occurrence correlated significantly with the sewage-polluted area, but HAdVs were only found in autumn and AstVs in spring. Meanwhile, enteric viruses in the swimming area showed significantly higher levels than the surrounding area, particularly AstVs in summer with the swimmer crowd. All these data imply that sewage discharge and swimmers co-contribute to the viral occurrence in a seasonal pattern, with the former being more focused in warm seasons (spring and autumn) and the latter in hot seasons (summer). These results indicate that sewage discharge and crowd swimmers, as unsafe swimming conditions, should be avoided to improve public health at the bathing beaches.

Chlorine disinfection promotes the exchange of antibiotic resistance genes across bacterial genera by natural transformation.

Chlorine disinfection to drinking water plays an important role in preventing and controlling waterborne disease outbreaks globally. Nevertheless, little is known about why it enriches the antibiotic resistance genes (ARGs) in bacteria after chlorination. Here, ARGs released from killed antibiotic-resistant bacteria (ARB), and culturable chlorine-injured bacteria produced in the chlorination process as the recipient, were investigated to determine their contribution to the horizontal transfer of ARGs during disinfection treatment. We discovered Escherichia coli, Salmonella aberdeen, Pseudomonas aeruginosa and Enterococcus faecalis showed diverse resistance to sodium hypochlorite, and transferable RP4 could be released from killed sensitive donor consistently. Meanwhile, the survival of chlorine-tolerant injured bacteria with enhanced cell membrane permeabilisation and a strong oxidative stress-response demonstrated that a physiologically competent cell could be transferred by RP4 with an improved transformation frequency of up to 550 times compared with the corresponding untreated bacteria. Furthermore, the water quality factors involving chemical oxygen demand (CODMn), ammonium nitrogen and metal ions (Ca2+ and K+) could significantly promote above transformation frequency of released RP4 into injured E. faecalis. Our findings demonstrated that the chlorination process promoted the horizontal transfer of plasmids by natural transformation, which resulted in the exchange of ARGs across bacterial genera and the emergence of new ARB, as well as the transfer of chlorine-injured opportunistic pathogen from non-ARB to ARB. Considering that the transfer elements were quite resistant to degradation through disinfection, this situation poses a potential risk to public health.

Putative environmental levels of levofloxacin facilitate the dissemination of antibiotic-resistant Escherichia coli via plasmid-mediated transformability.

Antibiotic residues in the environment pose a great risk to global public health. They increase antibiotic resistance by enhancing plasmid conjugation among bacteria or mutations within bacterial genomes. However, little is known about whether the putative environmental levels of antibiotics are sufficient to influence plasmid-mediated transformability. In this study, we explored the effect of eight kinds of representative antibiotics and several other compounds on the plasmid transformability of competent Escherichia coli. Only levofloxacin (LEV) at the putative environmental levels was found to facilitate the frequency of PBR322-or RP4-plasmid-mediated transformation by up to 5.3-fold. Additionally, PBR322 transformation frequency could be further enhanced by copper ion or ammonia nitrogen but inhibited by humic acid. However, when competent E. coli was exposed to the minimal inhibitory concentrations (MIC) of the antibiotics, an enhanced plasmid-assimilation ability was observed and plasmid transformation frequency was increased by up to 98.6-fold for all the tested antibiotics. Furthermore, E. coli exhibited a preference for the uptake of plasmids harbouring the resistance genes to the antibiotics it had been exposed to. Among these antibiotics, cephalexin, tetracycline, and kanamycin induced the highest uptake of RP4. The putative environmental levels of LEV enhanced plasmid transformability regardless of the presence of corresponding antibiotic resistance gene (ARG) on the genetic elements, suggesting environmental LEV residues may facilitate dissemination of antibiotic resistance by any plasmid-mediated transformability, thereby posing a great risk to health.

Comparison of a Novel Tension Band and Patellotibial Tubercle Cerclage in the Treatment of Comminuted Fractures of Inferior Pole of the Patella.

OBJECTIVE: To assess the therapeutic effect of a novel tension band using 3.0 mm cannulated screw combined with a titanium cable and specific shims comparatively with patellotibial tubercle cerclage in comminuted fractures of the inferior pole of the patella. METHODS: The retrospective study from March 2012 to July 2017 was conducted in Peking University Third Hospital and comprised 63 patients with comminuted fractures of the inferior pole of the patella: 41 treated with new tension band using 3.0 mm cannulated screw combined with a titanium cable and specific shims (new tension band group) and 22 with patellotibial tubercle cerclage (tubercle cerclage group). Gender, age, AO/OTA fracture type, injury mechanism, inter-fragmentary gap, and follow-up time of patients were recorded. Two groups were compared regarding: operation time, blood loss, partial weight-bearing time, fracture-healed time, Bostman score and knee mobility at 12-month follow-up, and postoperative complications. Continuous and categorical parameters were analyzed by Mann-Whitney U test and the chi-squared test, respectively. Fisher's exact test was used for small data subsets. RESULTS: Between the two groups, no statistically significant difference was found in mean age, gender, AO/OTA fracture type, injury mechanism, mean inter-fragmentary gap, or mean follow-up time (P > 0.05). The mean operation time of new tension band group was significantly longer than that of tubercle cerclage group (76.4 min vs 64.2 min, P = 0.006), while there was no significant difference in blood loss. After surgery, new tension band group had a significantly earlier mean partial weight-bearing time (5.2 weeks vs 7.4 weeks, P < 0.001) and fracture-healed time (9.6 weeks vs 11.6 weeks, P < 0.001). At 12-month follow-up, patients of new tension band group had a significantly higher mean Bostman score (28.5 vs 25.8, P < 0.001) and knee mobility (126.7 vs 117.3, P < 0.001). Ten complications related with internal fixation were found in tubercle cerclage group including two cases of loose internal fixation, two cases of cerclage breakage, and six cases of low patella position who undertook secondary operation. No complications were found in new tension band group (0 in 41 vs 10 in 22, P < 0.001). CONCLUSION: Patients with comminuted fractures of the inferior pole of the patella treated with a novel tension band experienced a longer operation time, but earlier partial-weight-bearing and fracture-healed time, better clinical outcomes at 12-month follow-up, and less complications. It should be considered an alternative therapy for the treatment of distal pole patellar fractures.

Loss of the posteromedial support: a risk factor for implant failure after fixation of AO 31-A2 intertrochanteric fractures.

BACKGROUND: The purpose of this study was to analyze cases of AO31-A2 intertrochanteric fractures (ITFs) and to identify the relationship between the loss of the posteromedial support and implant failure. METHODS: Three hundred ninety-four patients who underwent operative treatment for ITF from January 2003 to December 2017 were enrolled. Focusing on posteromedial support, the A2 ITFs were divided into two groups, namely, those with (Group A, n = 153) or without (Group B, n = 241) posteromedial support post-operatively, and the failure rates were compared. Based on the final outcomes (failed or not), we allocated all of the patients into two groups: failed (Group C, n = 66) and normal (Group D, n = 328). We separately analyzed each dataset to identify the factors that exhibited statistically significant differences between the groups. In addition, a logistic regression was conducted to identify whether the loss of posteromedial support of A2 ITFs was an independent risk factor for fixation failure. The basic factors were age, sex, American Society of Anesthesiologists (ASA) score, side of affected limb, fixation method (intramedullary or extramedullary), time from injury to operation, blood loss, operative time and length of stay. RESULTS: The failure rate of group B (58, 24.07%) was significantly higher than that of group A (8, 5.23%) (χ = 23.814, P < 0.001). Regarding Groups C and D, the comparisons of the fixation method (P = 0.005), operative time (P = 0.001), blood loss (P = 0.002) and length of stay (P = 0.033) showed that the differences were significant. The logistic regression revealed that the loss of posteromedial support was an independent risk factor for implant failure (OR = 5.986, 95% CI: 2.667-13.432) (P < 0.001). CONCLUSIONS: For AO31-A2 ITFs, the loss of posteromedial support was an independent risk factor for fixation failure. Therefore, posteromedial wall reconstruction might be necessary for the effective treatment of A2 fractures that lose posteromedial support.

Predictors and reduction techniques for irreducible reverse intertrochanteric fractures.

BACKGROUND: Reverse intertrochanteric fractures are usually initially treated with closed reduction. However, sometimes these fractures are not amenable to closed reduction and require open reduction. To date, few studies have been conducted on predictors of and reduction techniques for irreducible reverse intertrochanteric fractures. Therefore, this study aimed to summarize the displacement patterns of irreducible reverse intertrochanteric fractures and corresponding reduction techniques, and explore predictors of irreducibility. METHODS: We reviewed 1174 cases of trochanteric fractures treated in our hospital from January 2006 to October 2018, 113 of which were reverse intertrochanteric fractures. An irreducible fracture was determined according to intra-operative fluoroscopy imaging after closed manipulation. Fractures were assessed for displacement patterns, radiographic features of irreducibility, and reduction techniques. Logistic regression analysis was performed on potential predictors for irreducibility, including gender, age, body mass index, AO Foundation/Orthopaedic Trauma Association (AO/OTA) classification, and radiographic features. RESULTS: Seventy-six irreducible fractures were identified, accounting for 67% of reverse intertrochanteric fractures. Six patterns of fracture displacement after closed manipulation were identified; the most common pattern was medial displacement and posterior sagging of the femoral shaft relative to the head-neck fragment. Multivariate logistic regression analysis identified three predictors of irreducibility: a medially displaced femoral shaft relative to the head-neck fragment on the anteroposterior (AP) view (odds ratio [OR], 8.00; 95% confidence interval [CI], 3.04-21.04; P < 0.001), a displaced lesser trochanter (OR, 3.61; 95% CI, 1.35-9.61; P = 0.010), and a displaced lateral femoral wall (OR, 2.92; 95% CI, 1.02-8.34; P = 0.046). CONCLUSIONS: A high proportion of reverse intertrochanteric fractures are not amenable to closed reduction. Six patterns of fracture displacement after closed manipulation were identified. Different reduction techniques are required for different displacement patterns. Predictors of irreducibility include a medially displaced femoral shaft relative to the head-neck fragment on the AP view, a displaced lesser trochanter, and a displaced lateral femoral wall. These patients warrant special consideration in terms of recognition and management.

Inactivation of Poliovirus by Ozone and the Impact of Ozone on the Viral Genome.

OBJECTIVE: To investigate the mechanisms underlying ozone-induced inactivation of poliovirus type 1 (PV1). METHODS: We used cell culture, long-overlapping RT-PCR, and spot hybridization assays to verify and accurately locate the sites of action of ozone that cause PV1 inactivation. We also employed recombinant viral genome RNA infection models to confirm our observations. RESULTS: Our results indicated that ozone inactivated PV1 primarily by disrupting the 5'-non-coding region (5'-NCR) of the PV1 genome. Further study revealed that ozone specifically damaged the 80-124 nucleotide (nt) region in the 5'-NCR. Recombinant viral genome RNA infection models confirmed that PV1 lacking this region was non-infectious. CONCLUSION: In this study, we not only elucidated the mechanisms by which ozone induces PV1 inactivation but also determined that the 80-124 nt region in the 5'-NCR is targeted by ozone to achieve this inactivation.

Chlorine injury enhances antibiotic resistance in Pseudomonas aeruginosa through over expression of drug efflux pumps.

Adaption to adverse environments plays an important role in bacterial survival and is receiving increasing globe attention now. Here, cultivable chlorine-injured Pseudomonas aeruginosa, produced on the chlorination process, was investigated about their resistance to antibiotics. Then, global transcriptional analyses, quantitative PCR (qPCR) validation and antioxidant enzymes measurement were performed to explore the underlying mechanisms. The results showed that chlorine injury enhanced antibiotic resistance in P. aeruginosa and cultivable chlorine-injured P. aeruginosa exposed to 4 mg/L sodium hypochlorite (half of the lethal dose) improved antibiotic resistance against ceftazidime, chloramphenicol and ampicillin by 1.4-5.6 fold. This increase in antibiotic resistance was not hereditable and over expression of the MexEF-OprN efflux pump resulting from oxidative stress contributed to it. These results demonstrate temporal physiological persistence to antibiotics in cultivable chlorine-injured pathogens, suggesting their survival from adverse environments with antibiotic exposure and thereby posing lasting hazards to human health.

Profiling of intracellular and extracellular antibiotic resistance genes in tap water.

Antibiotic resistance genes (ARGs) have gained global attention due to their public health threat. Extracelluar ARGs (eARGs) can result in the dissemination of antibiotic resistance via free-living ARGs in natural environments, where they promote ARB transmission in drinking water distribution systems. However, eARG pollution in tap water has not been well researched. In this study, concentrations of eARGs and intracellular ARGs (iARGs) in tap water, sampled at Tianjin, China, were investigated for one year. Fourteen eARG types were found at the highest concentration of 1.3 × 105 gene copies (GC)/L. TetC was detected in 66.7% of samples, followed by sul1, sul2, and qnrA with the same detection frequency of 41.7%. Fifteen iARGs (including tetA, tetB, tetM, tetQ, tetX, sul1, sul2, sul3, ermB, blaTEM, and qnrA) were continuously detected in all collected tap water samples with sul1 and sul2 the most abundant. Additionally, both eARG and iARG concentrations in tap water presented a seasonal pattern with most abundant prevalence in summer. The concentration of observed intracellular sulfonamide resistance genes showed a significantly positive correlation with total nitrogen concentrations. This study suggested that eARG and iARG pollution of drinking water systems pose a potential risk to human public health.

Role of Kir6.2 subunits of ATP-sensitive potassium channels in endotoxemia-induced cardiac dysfunction.

BACKGROUND: Cardiac dysfunction is well-described in endotoxemia and diagnosed in up to 60% of patients with endotoxic shock. ATP-sensitive potassium (KATP) channels are critical to cardiac function. This study investigates the role of Kir6.2 subunits of KATP channels on cardiac dysfunction in lipopolysaccharide (LPS)-induced endotoxemia. METHODS: Kir6.2 subunits knockout (Kir6.2-/-) and wild-type (WT) mice were injected with LPS to induce endotoxemia. Cardiac function was monitored by echocardiography. Left ventricles were taken for microscopy (both light and electron) and TUNEL examination. Serum lactate dehydrogenase (LDH) and creatine kinase (CK) activities, and tumor necrosis factor-α (TNF-α) levels in both serum and left ventricular tissues were determined. RESULTS: Compared to WT, Kir6.2-/- mice showed significantly declined cardiac function 360 min after LPS administration, aggravated myocardial damage and elevated serum LDH and CK activities. Apoptotic cells were obviously increased in heart tissues from Kir6.2-/- mice at 90, 180 and 360 min. TNF-α expression in both serum and heart tissues of Kir6.2-/- mice was significantly increased. CONCLUSIONS: We conclude that Kir6.2 subunits are critical in resistance to endotoxemia-induced cardiac dysfunction through reducing myocardial damage by inhibition of apoptosis and inflammation. KATP channels blockers are extensively used in the treatment of diabetes, their potential role should therefore be considered in the clinic when patients treated with antidiabetic sulfonylureas are complicated by endotoxemia.

[Mutation analysis of beta myosin heavy chain gene in hypertrophic cardiomyopathy families].

OBJECTIVE: To detect the gene mutations of beta-myosin heavy chain gene (MYH7) in Chinese pedigrees with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between the genotype and phenotype. METHODS: Exons 3, 5, 7-9, 11-16 and 18-23 of the MYH7 gene were amplified with PCR in three Chinese pedigrees with HCM. The products were sequenced. Sequence alignment between the detected and the standard sequences was performed. RESULTS: A missense mutation of Thr441Met in exon 14 was identified in a pedigree, which was not detected in the controls. Several synonymous mutations of MYH7 gene were detected in the three pedigrees. CONCLUSION: The mutation of Thr441Met, located in the actin binding domain of the globular head, was first identified in Chinese. It probably caused HCM. HCM is a heterogeneous disease. Many factors are involved in the process of its occurrence and development.

Analysis of embryo, cytoplasmic and maternal genetic correlations for seven essential amino acids in rapeseed meal (Brassica napus L.).

Genetic correlations of nutrient quality traits including lysine, methionine, leucine, isoleucine, phenylalanine, valine and threonine contents in rapeseed meal were analysed by the genetic model for quantitative traits of diploid plants using a diallel design with nine parents of Brassica napus L. These results indicated that the genetic correlations of embryo, cytoplasm and/or maternal plant havemade different contribution to total genetic correlations of most pairwise nutrient quality traits. The genetic correlations among the amino acids in rapeseed meal were simultaneously controlled by genetic main correlations and genotype x environment (GE) interaction correlations, especially for the maternal dominance correlations. Most components of genetic main correlations and GE interaction correlations for the pairwise traits studied were significantly positive. Some of the pairwise traits had negative genetic correlations, especially between valine and other amino acid contents. Indirect selection for improving the quality traits of rapeseed meal could be expected in rape breeding according to the magnitude and direction of genetic correlation components.

[Screening and analysis of the mutations on beta-myosin heavy chain gene in 3 Chinese families with hypertrophic cardiomyopathy].

OBJECTIVE: To detect gene mutations on beta-myosin heavy chain gene MYH7 in 3 Chinese families with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between genotype and phenotype. METHODS: A denaturing high-performance liquid chromatography (DHPLC) and sequencing mutation screening of the exons (exon3-23) coding for MYH7 gene were performed in 3 Chinese families with HCM. RESULTS: In this study, we identified several mutations in MYH7. A mutation of Thr441Met previously reported in a patient with Laing distal myopathy was first identified in one Chinese pedigree. CONCLUSION: This study illustrated the high frequency of mutation in MYH7 gene in Chinese HCM families. Different mutations and carriers of the MYH7 gene present phenotypic heterogeneity. Mutation screening and analysis in HCM family could therefore facilitate the early HCM diagnosis and would be helpful for the prediction, prevention and early treatment of HCM linked with MYH7 gene mutation.

Role of vascular K(ATP) channels in blood pressure variability after sinoaortic denervation in rats.

AIM: To investigate the role of ATP-sensitive potassium (K(ATP)) channels on blood pressure variability (BPV) in sinoaortic denervated (SAD) rats. METHODS: SAD was performed on male Sprague-Dawley rats 4 weeks before the study. mRNA expression of Kir6.1, Kir6.2 and SUR2 in aorta and mesenteric artery was determined using real-time quantitative polymerase chain reaction, and confirmed at the protein level using Western blotting and laser confocal immunofluorescence assays. Concentration-response curves of isolated aortic and mesenteric arterial rings to adenosine and pinacidil were established. Effects of K(ATP) channel openers and blocker on BPV were examined in conscious SAD rats. RESULTS: Aortic SUR2 expression was significantly greater, while Kir6.1 was lower, in SAD rats than in sham-operated controls. In contrast, in the mesenteric artery both SUR2 and Kir6.1 expression were markedly lower in SAD rats than controls. For both arteries, Kir6.2 expression was indistinguishable between sham-operated and SAD rats. These findings were confirmed at the protein level. Responses of the aorta to both adenosine and pinacidil were enhanced after SAD, while the mesenteric response to adenosine was attenuated. Pinacidil, diazoxide, nicorandil, and glibenclamide significantly decreased BPV. CONCLUSION: These findings indicate that expression of vascular K(ATP) channels is altered by chronic SAD. These alterations influence vascular reactivity, and may play a role in the increased BPV in chronic SAD rats.

Dysfunction of the cholinergic anti-inflammatory pathway mediates organ damage in hypertension.

Inflammatory responses are associated with the genesis and progression of end-organ damage (EOD) in hypertension. A role for the α7 nicotinic acetylcholine receptor (α7nAChR) in inflammation has recently been identified. We tested the hypothesis that α7nAChR dysfunction contributes to hypertensive EOD. In both spontaneously hypertensive rats (SHRs) and rats with abdominal aorta coarctation-induced hypertension, atropine-induced tachycardia was blunted compared with normotensive controls. Both models of hypertension were associated with deficits in expression of the vesicular acetylcholine transporter and the α7nAChR in cardiovascular tissues. In hypertension induced by abdominal aorta coarctation, deficits in aortic vesicular acetylcholine transporter and α7nAChR were present both above and below the coarctation site, indicating that they were independent of the level of arterial pressure itself. Hypertension in 40-week-old SHRs was associated with cardiac and aortic hypertrophy. Morphological abnormalities consistent with EOD, along with elevated tissue levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, and interleukin-6) were observed in the heart, kidney, and aorta. Chronic treatment of SHRs with the α7nAChR agonist PNU-282987 relieved EOD and inhibited tissue levels of proinflammatory cytokines and activation of nuclear factor κB. Greater serum levels of proinflammatory cytokines and more severe damage in the heart, aorta, and kidney were seen in α7nAChR(-/-) mice subjected to 2-kidney-1-clip surgery than in wild-type mice. A deficit in the cholinergic anti-inflammatory pathway appears to contribute to the pathogenesis of EOD in models of hypertension of varying etiology. This pathway may provide a new target for preventing cardiovascular disease resulting from hypertension.

A potential role of alpha-7 nicotinic acetylcholine receptor in cardiac angiogenesis in a pressure-overload rat model.

This work investigated the expression of alpha-7 nicotinic acetylcholine receptor (α7nAChR) in the left ventricle and its putative role in cardiac angiogenesis in a pressure overload rat model induced by abdominal aorta coarctation. Blood pressure and protein levels of α7nAChR were measured at 4, 8, 12, and 16 weeks after surgery. mRNA levels of α7nAChR, cardiac vagus nerve function, cardiac hypertrophy, and microvessel density of the left ventricle were determined at the final 16-week period. The role of α7nAChR in angiogenesis was evaluated. It was found that systolic blood pressure above the coarctation site was greater at 16 weeks after coarctation and expression of α7nAChR was significantly increased at both mRNA and protein levels in the left ventricle compared with the control. Positive staining for receptors was mainly focused around vessels and among the degenerated cardiomyocytes. Cardiac vagus nerve function was significantly attenuated; microvessel density was markedly increased and was associated with cardiac hypertrophy. Activation of α7nAChR induced tube formation of cultured human umbilical vein endothelial cells (HUVECs). We conclude that expression of α7nAChR was increased at 16 weeks after coarctation, and this might be a compensatory response to decreased vagus nerve function and cardiac hypertrophy and may also play a role in cardiac angiogenesis.